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Simultaneous perturbation of multiple metabolic pathways by non-essential amino acid restriction is a potent cancer radio-sensitisation strategy

ABSTRACT: Simultaneous perturbation of multiple metabolic pathways by non-essential amino acid restriction is a potent cancer radio-sensitisation strategy

PROVIDER: PRJNA787936 | ENA |

REPOSITORIES: ENA

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Simultaneous perturbation of multiple metabolic pathways by non-essential amino acid restriction is a potent cancer radio-sensitisation strategy

Project description:Cellular metabolism is an integral component of cellular adaptation to stress, consequently, metabolism plays a pivotal role in the resistance of cancer cells to a range of treatment modalities. Radiotherapy is used to treat approximately half of all cancer patients, however, most are either inherently radioresistant or acquire resistance over time. Effective radiotherapy relies on generating an overwhelming burden of DNA damage which triggers cell death. In response to radiotherapy cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism we hypothesised that controlling the availability of the exogenous amino acids serine and glycine would be an effective strategy to radiosensitive cancer cells. Here we show that serine and glycine restriction sensitised a range of cancer cell lines, patient derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only glutathione and nucleotide synthesis but had an unexpected impact on the TCA cycle and antagonised a key cellular redox response to radiotherapy mediated by reductive carboxylation.

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Nasopharyngeal carcinoma patient samples: radio-sensitive samples vs. radio-resistant samples

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Comparison of gene expression in radio-resistant and radio-sensitive patient-derived spheroid cultures of small cell carcinoma of the cervix

Project description:We established panels of patient-derived culture of the cancer cells from small cell carcinoma of the cervix uteri (SCCC) by cancer tissueM-bM-^@M-^Soriginated spheroids (CTOS) method. Then we developed in vitro sensitivity assay for radiation using CTOSs to assess the intrinsic radio-sensitivity and mechanism of radio-resistance in individual SCCC patients. To find factors that affect to the radio-sensitivity we compared gene expression of radio-resistant CTOS (cerv-5) and radio-sensitive CTOS (cerv-9). We compared gene expression of cerv5 and cerv9 CTOSs under the culture condition.

2014-04-07 | E-GEOD-56540 | biostudies-arrayexpress

Comparison of gene expression in radio-resistant and radio-sensitive patient-derived spheroid cultures of small cell carcinoma of the cervix

Project description:We established panels of patient-derived culture of the cancer cells from small cell carcinoma of the cervix uteri (SCCC) by cancer tissue–originated spheroids (CTOS) method. Then we developed in vitro sensitivity assay for radiation using CTOSs to assess the intrinsic radio-sensitivity and mechanism of radio-resistance in individual SCCC patients. To find factors that affect to the radio-sensitivity we compared gene expression of radio-resistant CTOS (cerv-5) and radio-sensitive CTOS (cerv-9).

2014-04-07 | GSE56540 | GEO

Amino acid/Nucleotide perturbation in Escherichia coli

Project description:Wild-type E. coli are prototrophic for all amino acid and nucleotides. These are synthesized by a network of interconnected metabolic pathways from a handful precursors molecules, which are regulated at the level of gene expression. It was hypothesized in this study, that since metabolic pathways are interconnected, transcriptional regulation should be shared across multiple pathways. To uncover these regulatory interactions, cells growing at steady state were perturbed by the addition of an end-metabolite (aa or nt), and were allowed to recover. The adjustments in biochemical pathways to the perturbation were sampled by profiling mRNA abundance 10 minutes after the perturbation. By limiting the scope and magnitude of the perturbation, mRNA changes are expected to be limited to specific responses to the perturbation and not genome-wide changes associated with larger perturbations such as nutritional shifts and stresses.

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Expression data of the parental and the induced radio-resistant colorectal cancer cell lines

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2018-05-16 | PXD006701 | Pride

The immune suppressive tumor microenvironment affects efficacy of radio-immunotherapy in breast-to-brain metastasis

Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.

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